COL1A1 protein, human; Collagen Type I; Collagen Type I, alpha 1 Chain; Procollagen; Procollagen Type I; Arginine; Cysteine; Arginine/genetics; Child, Preschool; Collagen Type I, alpha 1 Chain/genetics; Humans; Mutation; Procollagen/genetics; Cysteine/genetics; Hyperostosis, Cortical, Congenital; Genetics (clinical)
Abstract :
[en] PURPOSE: Infantile Caffey disease is a rare disorder characterized by acute inflammation with subperiosteal new bone formation, associated with fever, pain, and swelling of the overlying soft tissue. Symptoms arise within the first weeks after birth and spontaneously resolve before the age of two years. Many, but not all, affected individuals carry the heterozygous pathogenic COL1A1 variant (c.3040C>T, p.(Arg1014Cys)).
METHODS: We sequenced COL1A1 in 28 families with a suspicion of Caffey disease and performed ultrastructural, immunocytochemical, and biochemical collagen studies on patient skin biopsies.
RESULTS: We identified the p.(Arg1014Cys) variant in 23 families and discovered a novel heterozygous pathogenic COL1A1 variant (c.2752C>T, p.(Arg918Cys)) in five. Both arginine to cysteine substitutions are located in the triple helical domain of the proα1(I) procollagen chain. Dermal fibroblasts (one patient with p.(Arg1014Cys) and one with p.(Arg918Cys)) produced molecules with disulfide-linked proα1(I) chains, which were secreted only with p.(Arg1014Cys). No intracellular accumulation of type I procollagen was detected. The dermis revealed mild ultrastructural abnormalities in collagen fibril diameter and packing.
CONCLUSION: The discovery of this novel pathogenic variant expands the limited spectrum of arginine to cysteine substitutions in type I procollagen. Furthermore, it confirms allelic heterogeneity in Caffey disease and impacts its molecular confirmation.
Disciplines :
Genetics & genetic processes
Author, co-author :
Dhooge, Tibbe ; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent University Hospital, Ghent, Belgium
Syx, Delfien; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent University Hospital, Ghent, Belgium
Hermanns-Lê, Trinh ; Department of Dermatopathology, University Hospital of Sart-Tilman, Liège University, Liège, Belgium
Hausser, Ingrid; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Mortier, Geert; Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
Zonana, Jonathan; Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR, USA
Symoens, Sofie; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent University Hospital, Ghent, Belgium
Byers, Peter H; Department of Pathology and Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
Malfait, Fransiska ; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent University Hospital, Ghent, Belgium. Fransiska.Malfait@UGent.be
Language :
English
Title :
Caffey disease is associated with distinct arginine to cysteine substitutions in the proα1(I) chain of type I procollagen.
We thank all the patients and the referring physicians. D.S. and F.M. are fellows of the Research Foundation, Flanders (FWO). T.D. has a BOF doctoral fellowship from Ghent University. This study was financially supported by Ghent University (Methusalem grant BOFMET2015000401) and with funds from the Collagen Diagnostic Laboratory, Department of Pathology, University of Washington.
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